Several metal-based carbon monoxide-releasing molecules (CORMs) are active CO donors with established antibacterial activity. Among them, CORM conjugates with azole antibiotics of type [Mn(CO)₃(2,2′-bipyridyl)(azole)]⁺ display important synergies against several microbes. We carried out a structure–activity relationship study based upon the lead structure of [Mn(CO)₃(Bpy)(Ctz)]⁺ by producing clotrimazole (Ctz) conjugates with varying metal and ligands. We concluded that the nature of the bidentate ligand strongly influences the bactericidal activity, with the substitution of bipyridyl by small bicyclic ligands leading to highly active clotrimazole conjugates. On the contrary, the metal did not influence the activity. We found that conjugate [Re(CO)₃(Bpy)(Ctz)]⁺ is more than the sum of its parts: while precursor [Re(CO)₃(Bpy)Br] has no antibacterial activity and clotrimazole shows only moderate minimal inhibitory concentrations, the potency of [Re(CO)₃(Bpy)(Ctz)]⁺ is one order of magnitude higher than that of clotrimazole, and the spectrum of bacterial target species includes Gram-positive and Gram-negative bacteria. The addition of [Re(CO)₃(Bpy)(Ctz)]⁺ to Staphylococcus aureus causes a general impact on the membrane topology, has inhibitory effects on peptidoglycan biosynthesis, and affects energy functions. The mechanism of action of this kind of CORM conjugates involves a sequence of events initiated by membrane insertion, followed by membrane disorganization, inhibition of peptidoglycan synthesis, CO release, and break down of the membrane potential. These results suggest that conjugation of CORMs to known antibiotics may produce useful structures with synergistic effects that increase the conjugate’s activity relative to that of the antibiotic alone.

In the last decade, carbon monoxide-releasing molecules (CORMs) have been shown to act against several pathogens and to be promising antimicrobials. However, the understanding of the mode of action and reactivity of these compounds on bacterial cells is still deficient. In this work, we used a metabolomics approach to probe the toxicity of the ruthenium(II) complex Ru(CO) ₃ Cl(glycinate) (CORM-3) on Escherichia coli .

The complex Ru([9]aneS₃)(gly)Cl (gly = glycine) was obtained from the reaction of the precursor Ru([9]aneS₃)dmsoCl₂ with glycine and encapsulated into native β-CD, a hydroxypropylated derivative HPβCD, and the methylated cyclodextrins TRIMEB and CRYSMEB. All four inclusion compounds were obtained with a 1:1 host:guest stoichiometry and characterised in the solid-state by powder X-ray diffraction, thermogravimetric analysis (TGA), and ¹³C{¹H} CP/MAS NMR and FTIR spectroscopies. The cytostatic and antiproliferative activity of the complex Ru([9]aneS₃)(gly)Cl and its four CD inclusion compounds was tested on the human osteosarcoma MG-63 cell line and the results compared to the inhibitory effect exerted by the pure cyclodextrins.